Human T-cell lymphotropic virus type I (HTLV-I) is associated with two human diseases, adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). Lymphocytes from both ATL and TSP/HAM patients display abnormal proliferation properties in culture. Purified, soluble Taxl protein can be taken up by, and stimulate proliferation of, uninfected phytohemagglutinin-treated human peripheral blood lymphocytes (PBLs). Taxl was 40-70% as active as IL-2 in stimulating proliferation of PBLs. Heat-inactivated or chloro- form-extracted Taxl failed to stimulate PBL proliferation. Taxl could not stimulate proliferation of PBLs in the absence of PHA. Following an initial round of cell division, Taxl-treated PBLs exhibited prolonged sensitivity to interleukin-2-induced proliferation. These results indicate that Taxl can stimulate lymphocyte proliferation in culture and imply that extracellular Taxl may be involved in the spontaneous proliferation of TSP/HAM lymphocytes and the interleukin-2-dependent proliferation of ATL lymphocytes.